Phosphatidylserine (PS) is localized on the inner leaflet of the lipid bilayer of most cells. As a cell apoptoses, PS becomes exposed on its outer leaflet. Exposed PS is recognized by PS receptors on phagocytes, which respond by engulfing the apoptotic cell. Viruses with lipid envelopes lack enzymes that maintain bilayer asymmetry and thus have exposed PS. We have shown that many - but not all - enveloped viruses exploit PS receptors to enter cells. For example, the efficiency of influenza A virus infection is not affected by PS receptors expression on the target cells. In contrast, infection of cells by dengue or West Nile viruses is markedly enhanced when cells express PS receptors. This observation is somewhat surprising, because, in their so-called mature states, the phospholipid bilayer of flaviviruses is largely occluded by a proteinaceous exoskeleton. This suggests that PS receptors primarily engage viral particles when the virion membrane is better exposed, for example when the virion particle is in its partially immature mosaic state, in its pre-fusogenic bumpy state or in a transient low-pH induced fusogenic state. Each of these conformational states imposes distinct steric restraints on PS receptor association, perhaps explaining why flaviviruses only utilize a subset of PS receptors, whereas other viruses are less selective. This selectivity, and the potency with which some PS receptors promote flavivirus infection, suggest that a small number of PS receptors might be effectively targeted to treat dengue or West Nile virus infections. Accordingly, our proposal has two specific aims. In Specific Aim 1 we will determine which PS receptors most contribute to flavivirus infections in vivo, and whether the absence or blockade of these receptors can slow a flavivirus infection. In Specific Aim 2 we will explore how flaviviruses utilize PS receptors by answering several questions: Which conformational states of the virion are involved? Do flaviviruses actively increase PS incorporation into the lipid membrane of the virion? What are the downstream consequences of PS receptor ligation? How does PS receptor utilization impact transmission from vector to host? Collectively, these studies will determine which PS receptors might be good targets for therapies that control dengue and West Nile virus infections, and provide mechanistic insight useful for developing these therapies.